The HRS/J mouse is an inbred genetically immuno-deficient strain which carries a mutant gene, hr, located on chromosome 14, linkage group III. Strain HRS/J originated from a cross between a random-bred strain carrying the mutation hr and the BALB/cGn strain and consists of 3 genotypes, hr/hr, hr/+and +/+. Meier, H., D. D. Myers, and R. J. Hueber, 1969. "Genetic control by the hr-locus of susceptibility and resistance to leukemia." PNAS 63:759 (1969). A severe thymic cortical atrophy observed in homozygous hr/hr mice beginning at about 6 months of age with specific defects of the immune system is indicated by 1) a deficiency in their ability to produce antibody to tetanus toxoid and to respond to graft-vs-host reaction and T cell mitogens; 2) a disproportion of Ly-1,2,3+ and Ly-1+ cells; and, 3) an increased susceptibility to challenge with a syngeneic transplantable leukemia.
Peritoneal macrophages in primary cell culture derived from immuno-deficient HRS/J hairless mice can be employed to measure in a quantitative manner the biological activity of natural and synthetic substances which affect cell-mediated immune function. Spreading and phagocytosis are well characterized means of assessing activation kinetics of the mononuclear phagocyte cell line. Harrington-Fowler L. and Wilder, M. S. "Fate of Listeria monocytogenes in murine peritoneal macrophage subpopulations." Infec. Immun. 35:124:132 (1982). It recently has been demonstrated that the HRS/J homozygotes and heterozygous littermates possess unusual susceptibility to infection with facilitative intracellular parasites such as Candida albicans, Staphylococcus aureus, and Listeria monocytogenes.
Moreover, HRS/J-derived peritoneal macrophages express reduced bactericidal and oxidative activities when compared with mononuclear phagocytes obtained from immune competent mice.
Similar to that employed with the HRS/J macrophage, significant information relative to the diagnosis and treatment response of primary and secondary immunodeficiencies in humans to biological response modifiers may be generated using techniques which measure mononuclear phagocyte activation. The term macrophage as used here refers to all cells of the mononuclear phagocyte lineage, both circulating and localized throughout various tissue/organ systems.
Macrophages possess both anti-microbial and anti-tumor activity. Macrophages are responsible for the induction of response to antigen as well as the expression of cell-mediated immune response to microbial parasites and/or neoplastic cells.
Thymostimulin, a thymic extract also known as TP-1.RTM., has been shown to partially restore phagocytosis of latex particles by peripheral blood monocytes from patients with tuberculosis. Ippoliti, F.; DiGiovamballista, A. M.; Ferri, A. M.; Naso, G.; Ottaviani, C.; Spina, A.; Fiorani, C. M.; Arienzo, F; and Florucci, F. "Dysphagocytosis in Pulmonary Tuberculosis and its Partial Restoration by TP-1.RTM. in Vitro," 5th Eur. Immunol. Mtg., Istambul, Turkey, June 1-4 (1982).
All references cited herein are hereby incorporated by reference.